ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 15 mg prolonged-release tablets RINVOQ 30 mg prolonged-release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

RINVOQ 15 mg prolonged-release tablets

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg of upadacitinib.

RINVOQ 30 mg prolonged-release tablets

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg of upadacitinib.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Prolonged-release tablet

RINVOQ 15 mg prolonged-release tablets

Purple 14 x 8 mm, oblong biconvex prolonged-release tablets imprinted on one side with ‘a15’.

RINVOQ 30 mg prolonged-release tablets

Red 14 x 8 mm, oblong biconvex prolonged-release tablets imprinted on one side with ‘a30’.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Rheumatoid arthritis

RINVOQ is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate.

Psoriatic arthritis

RINVOQ is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more DMARDs. RINVOQ may be used as monotherapy or in combination with methotrexate.

2 Ankylosing spondylitis

RINVOQ is indicated for the treatment of active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy.

Atopic dermatitis

RINVOQ is indicated for the treatment of moderate to severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy.

4.2 Posology and method of administration

Treatment with upadacitinib should be initiated and supervised by physicians experienced in the diagnosis and treatment of conditions for which upadacitinib is indicated.

Posology

Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis The recommended dose of upadacitinib is 15 mg once daily.

Consideration should be given to discontinuing treatment in patients with ankylosing spondylitis who have shown no clinical response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.

Atopic dermatitis

Adults The recommended dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation.

• A dose of 30 mg once daily may be appropriate for patients with high disease burden. • A dose of 30 mg once daily may be appropriate for patients with an inadequate response to 15 mg once daily. • The lowest effective dose for maintenance should be considered.

For patients ≥ 65 years of age, the recommended dose is 15 mg once daily.

Adolescents (from 12 to 17 years of age) The recommended dose of upadacitinib is 15 mg once daily for adolescents weighing at least 30 kg.

Concomitant topical therapies Upadacitinib can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used for sensitive areas such as the face, neck, and intertriginous and genital areas.

Consideration should be given to discontinuing upadacitinib treatment in any patient who shows no evidence of therapeutic benefit after 12 weeks of treatment.

Dose initiation

Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) that is < 0.5 x 109 cells/L, an absolute neutrophil count (ANC) that is < 1 x 109 cells/L or who have haemoglobin (Hb) levels that are < 8 g/dL (see sections 4.4 and 4.8).

3 Dose interruption

Treatment should be interrupted if a patient develops a serious infection until the infection is controlled.

Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 1.

Table 1. Laboratory measures and monitoring guidance

Laboratory Monitoring guidance measure Action Treatment should be Evaluate at baseline and then no later than 12 weeks interrupted if ANC is after initiation of treatment. Thereafter evaluate Absolute < 1 x 109 cells/L and according to individual patient management. Neutrophil Count may be restarted once (ANC) ANC returns above this value Treatment should be interrupted if ALC is Absolute < 0.5 x 109 cells/L Lymphocyte and may be restarted Count (ALC) once ALC returns above this value Treatment should be interrupted if Hb is < 8 g/dL and may be Haemoglobin (Hb) restarted once Hb returns above this value Treatment should be Evaluate at baseline and thereafter according to temporarily routine patient management. Hepatic interrupted if drug- transaminases induced liver injury is suspected Patients should be 12 weeks after initiation of treatment and thereafter managed according according to international clinical guidelines for Lipids to international hyperlipidaemia clinical guidelines for hyperlipidaemia

Special populations

Elderly

For atopic dermatitis, doses higher than 15 mg once daily are not recommended in patients aged 65 years and older (see Section 4.8).

There are limited data in patients aged 75 years and older.

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. There are limited data on the use of upadacitinib in subjects with severe renal impairment (see section 5.2). Upadacitinib 15 mg once daily should be used with caution in patients with severe renal impairment. Upadacitinib

4 30 mg once daily is not recommended for patients with severe renal impairment. The use of upadacitinib has not been studied in subjects with end stage renal disease.

Hepatic impairment

No dose adjustment is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment (see section 5.2). Upadacitinib should not be used in patients with severe (Child- Pugh C) hepatic impairment (see section 4.3).

Paediatric population

The safety and efficacy of RINVOQ in children with atopic dermatitis below the age of 12 years have not been established. No data are available. No clinical exposure data are available in adolescents < 40 kg (see section 5.2).

The safety and efficacy of RINVOQ in children and adolescents with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis aged 0 to less than 18 years have not yet been established. No data are available.

Method of administration

RINVOQ is to be taken orally once daily with or without food and may be taken at any time of the day. Tablets should be swallowed whole and should not be split, crushed, or chewed in order to ensure the entire dose is delivered correctly.

4.3 Contraindications

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Active tuberculosis (TB) or active serious infections (see section 4.4).  Severe hepatic impairment (see section 4.2).  Pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

Immunosuppressive medicinal products

Combination with other potent immunosuppressants such as azathioprine, ciclosporin, tacrolimus, and biologic DMARDs or other Janus kinase (JAK) inhibitors has not been evaluated in clinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded.

Serious infections

Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The most frequent serious infections reported with upadacitinib included pneumonia and cellulitis (see section 4.8). Cases of bacterial meningitis have been reported in patients receiving upadacitinib. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/oesophageal candidiasis, and cryptococcosis were reported with upadacitinib.

Upadacitinib should not be initiated in patients with an active, serious infection, including localised infections.

Consider the risks and benefits of treatment prior to initiating upadacitinib in patients:

 with chronic or recurrent infection  who have been exposed to tuberculosis  with a history of a serious or an opportunistic infection

5  who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or  with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib. Upadacitinib therapy should be interrupted if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with upadacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and upadacitinib therapy should be interrupted if the patient is not responding to antimicrobial therapy. Upadacitinib therapy may be resumed once the infection is controlled.

As there is a higher incidence of infections in the elderly ≥ 65 years of age, caution should be used when treating this population.

Tuberculosis

Patients should be screened for tuberculosis (TB) before starting upadacitinib therapy. Upadacitinib should not be given to patients with active TB (see section 4.3). Anti-TB therapy should be considered prior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with risk factors for TB infection.

Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

Patients should be monitored for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

Viral reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was reported in clinical studies (see section 4.8). The risk of herpes zoster appears to be higher in Japanese patients treated with upadacitinib. If a patient develops herpes zoster, interruption of upadacitinib therapy should be considered until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving upadacitinib, a liver specialist should be consulted.

Vaccination

No data are available on the response to vaccination with live or inactivated vaccines in patients receiving upadacitinib. Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy is not recommended. Prior to initiating upadacitinib, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations, in agreement with current immunisation guidelines.

Malignancy

The risk of malignancies, including lymphoma is increased in patients with rheumatoid arthritis. Immunomodulatory medicinal products may increase the risk of malignancies, including lymphoma. The clinical data are currently limited and long-term studies are ongoing.

Malignancies were observed in clinical studies of upadacitinib. The risks and benefits of upadacitinib treatment should be considered prior to initiating therapy in patients with a known malignancy other

6 than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing upadacitinib therapy in patients who develop a malignancy.

Non-melanoma skin cancer

NMSCs have been reported in patients treated with upadacitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Haematological abnormalities

Absolute Neutrophil Count (ANC) < 1 x 109 cells/L, Absolute Lymphocyte Count (ALC) < 0.5 x 109 cells/L and haemoglobin < 8 g/dL were reported in ≤1 % of patients in clinical trials (see section 4.8). Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC < 1 x 109 cells/L, ALC < 0.5 x 109 cells/L or haemoglobin < 8 g/dL observed during routine patient management (see section 4.2).

Cardiovascular risk

Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients treated with upadacitinib should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care.

Lipids

Treatment with upadacitinib was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol (see section 4.8). Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy, although evidence is limited. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined (see section 4.2 for monitoring guidance).

Hepatic transaminase elevations

Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo.

Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury.

If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, upadacitinib therapy should be interrupted until this diagnosis is excluded.

Venous thromboembolism

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including upadacitinib. Upadacitinib should be used with caution in patients at high risk for DVT/PE. Risk factors that should be considered in determining the patient’s risk for DVT/PE include older age, obesity, a medical history of DVT/PE, patients undergoing major surgery, and prolonged immobilisation. If clinical features of DVT/PE occur, upadacitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.

7 4.5 Interaction with other medicinal products and other forms of interaction

Potential for other medicinal products to affect the pharmacokinetics of upadacitinib

Upadacitinib is metabolised mainly by CYP3A4. Therefore, upadacitinib plasma exposures can be affected by medicinal products that strongly inhibit or induce CYP3A4.

Coadministration with CYP3A4 inhibitors

Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, and clarithromycin). In a clinical study, coadministration of upadacitinib with ketoconazole resulted in 70% and 75% increases in upadacitinib Cmax and AUC, respectively. Upadacitinib 15 mg once daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. Upadacitinib 30 mg once daily dose is not recommended for patients receiving chronic treatment with strong CYP3A4 inhibitors. Alternatives to strong CYP3A4 inhibitor medications should be considered when used in the long-term.

Coadministration with CYP3A4 inducers

Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such as rifampin and phenytoin), which may lead to reduced therapeutic effect of upadacitinib. In a clinical study, coadministration of upadacitinib after multiple doses of rifampicin (strong CYP3A inducer) resulted in approximately 50% and 60% decreases in upadacitinib Cmax and AUC, respectively. Patients should be monitored for changes in disease activity if upadacitinib is co-administered with strong CYP3A4 inducers.

Methotrexate and pH modifying medicinal products (e.g., antacids or proton pump inhibitors) have no effect on upadacitinib plasma exposures.

Potential for upadacitinib to affect the pharmacokinetics of other medicinal products

Administration of multiple 30 mg once daily doses of upadacitinib to healthy subjects had a limited effect on midazolam (sensitive substrate for CYP3A) plasma exposures (26% decrease in midazolam AUC and Cmax), indicating that upadacitinib 30 mg once daily may have a weak induction effect on CYP3A. In a clinical study, rosuvastatin and atorvastatin AUC were decreased by 33% and 23%, respectively, and rosuvastatin Cmax was decreased by 23% following the administration of multiple 30 mg once daily doses of upadacitinib to healthy subjects. Upadacitinib had no relevant effect on atorvastatin Cmax or on plasma exposures of ortho-hydroxyatorvastatin (major active metabolite for atorvastatin). No dose adjustment is recommended for CYP3A substrates or for rosuvastatin or atorvastatin when coadministered with upadacitinib.

Upadacitinib has no relevant effects on plasma exposures of ethinylestradiol, levonorgestrel, methotrexate, or medicinal products that are substrates for metabolism by CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception during treatment and for 4 weeks following the final dose of upadacitinib. Female paediatric patients and/or their parents/caregivers should be informed about the need to contact the treating physician once the patient experiences menarche while taking upadacitinib.

8 Pregnancy

There are no or limited data on the use of upadacitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Upadacitinib was teratogenic in rats and rabbits with effects in bones in rat foetuses and in the heart in rabbit foetuses when exposed in utero.

Upadacitinib is contraindicated during pregnancy (see section 4.3).

If a patient becomes pregnant while taking upadacitinib the parents should be informed of the potential risk to the foetus.

Breast-feeding

It is unknown whether upadacitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk (see section 5.3).

A risk to newborns/infants cannot be excluded.

Upadacitinib should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue upadacitinib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of upadacitinib on human fertility has not been evaluated. Animal studies do not indicate effects with respect to fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Upadacitinib has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

In the placebo-controlled clinical trials for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, the most commonly reported adverse reactions (≥2% of patients in at least one of the indications with the highest rate among indications presented) with upadacitinib 15 mg were upper respiratory tract infections (19.5%), blood creatine phosphokinase (CPK) increased (8.6%), alanine transaminase increased (4.3%), bronchitis (3.9%), nausea (3.5%), cough (2.2%), aspartate transaminase increased (2.2%), and hypercholesterolaemia (2.2%).

In the placebo-controlled atopic dermatitis clinical trials, the most commonly reported adverse reactions (≥2% of patients) with upadacitinib 15 mg or 30 mg were upper respiratory tract infection (25.4%), acne (15.1%), herpes simplex (8.4%), headache (6.3%), CPK increased (5.5%), cough (3.2%), folliculitis (3.2%), abdominal pain (2.9%), nausea (2.7%), neutropenia (2.3%), pyrexia (2.1%), and influenza (2.1%).

The most common serious adverse reactions were serious infections (see section 4.4).

The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications.

9 Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical studies. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100). The frequencies in Table 2 are based on the higher of the rates for adverse reactions reported with RINVOQ 15 mg in rheumatologic disease and atopic dermatitis clinical trials, or RINVOQ 30 mg in atopic dermatitis clinical trials. When notable differences in frequency were observed between indications, these are presented in the footnotes below the table.

Table 2. Adverse reactions

System Organ Class Very common Common Uncommon Infections and Upper respiratory Bronchitisa,b Pneumonia infestations tract infections Herpes zoster Oral candidiasis (URTI)a Herpes simplexa Folliculitis Influenza Blood and lymphatic Anaemia system disorders Neutropaenia Metabolism and Hypercholesterolaemiab Hypertriglyceridaemia nutrition disorders Respiratory, thoracic Cough and mediastinal disorders Gastrointestinal Abdominal paina disorders Nausea Skin and subcutaneous Acnec Urticariac tissue disorders General disorders and Fatigue administration site Pyrexia conditions Investigations Blood CPK increased ALT increasedb AST increasedb Weight increased Nervous system Headache disorders

a Presented as grouped term b In atopic dermatitis trials, the frequency of bronchitis, hypercholesterolaemia, ALT increased, and AST increased was uncommon. c In rheumatologic disease trials, the frequency was common for acne and uncommon for urticaria.

Description of selected adverse reactions

Rheumatoid arthritis

Infections

In placebo-controlled clinical studies with background DMARDs, the frequency of infection over 12/14 weeks in the upadacitinib 15 mg group was 27.4% compared to 20.9% in the placebo group. In methotrexate (MTX)-controlled studies, the frequency of infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group was 19.5% compared to 24.0% in the MTX group. The overall

10 long-term rate of infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies (2,630 patients) was 93.7 events per 100 patient-years.

In placebo-controlled clinical studies with background DMARDs, the frequency of serious infection over 12/14 weeks in the upadacitinib 15 mg group was 1.2% compared to 0.6% in the placebo group. In MTX-controlled studies, the frequency of serious infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group was 0.6% compared to 0.4% in the MTX group. The overall long-term rate of serious infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 3.8 events per 100 patient-years. The most common serious infection was pneumonia. The rate of serious infections remained stable with long-term exposure.

Opportunistic infections (excluding tuberculosis)

In placebo-controlled clinical studies with background DMARDs, the frequency of opportunistic infections over 12/14 weeks in the upadacitinib 15 mg group was 0.5% compared to 0.3% in the placebo group. In MTX-controlled studies, there were no cases of opportunistic infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group and 0.2% in the MTX group. The overall long- term rate of opportunistic infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 0.6 events per 100 patient-years.

The long-term rate of herpes zoster for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 3.7 events per 100 patient-years. Most of the herpes zoster events involved a single dermatome and were non-serious. Hepatic transaminase elevations

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with upadacitinib 15 mg, compared to 1.5% and 0.7%, respectively, of patients treated with placebo. Most cases of hepatic transaminase elevations were asymptomatic and transient.

In MTX-controlled studies, for up to 12/14 weeks, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with upadacitinib 15 mg, compared to 1.9% and 0.9%, respectively, of patients treated with MTX.

The pattern and incidence of elevation in ALT/AST remained stable over time including in long-term extension studies.

Lipid elevations

Upadacitinib 15 mg treatment was associated with increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol and HDL cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 2 to 4 weeks of treatment and remained stable with longer-term treatment. Among patients in the controlled studies with baseline values below the specified limits, the following frequencies of patients were observed to shift to above the specified limits on at least one occasion during 12/14 weeks (including patients who had an isolated elevated value):

 Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 62% vs. 31%, in the upadacitinib 15 mg and placebo groups, respectively  LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 42% vs. 19%, in the upadacitinib 15 mg and placebo groups, respectively  HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 89% vs. 61%, in the upadacitinib 15 mg and placebo groups, respectively  Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 25% vs. 15%, in the upadacitinib 15 mg and placebo groups, respectively

11 Creatine phosphokinase

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, increases in CPK values were observed. CPK elevations > 5 x upper limit of normal (ULN) were reported in 1.0% and 0.3% of patients over 12/14 weeks in the upadacitinib 15 mg and placebo groups, respectively. Most elevations > 5 x ULN were transient and did not require treatment discontinuation. Mean CPK values increased by 4 weeks with a mean increase of 60 U/L at 12 weeks and then remained stable at an increased value thereafter including with extended therapy.

Neutropaenia

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases in neutrophil counts below 1 x 109 cells/L in at least one measurement occurred in 1.1% and <0.1% of patients in the upadacitinib 15 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ANC < 1 x 109 cells/L (see section 4.2). Mean neutrophil counts decreased over 4 to 8 weeks. The decreases in neutrophil counts remained stable at a lower value than baseline over time including with extended therapy.

Psoriatic arthritis

Overall, the safety profile observed in patients with active psoriatic arthritis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. A higher rate of serious infections (2.6 events per 100 patient-years and 1.3 events per 100 patient-years, respectively) and hepatic transaminase elevations (ALT elevations Grade 3 and higher rates 1.4% and 0.4%, respectively) was observed in patients treated with upadacitinib in combination with MTX therapy compared to patients treated with monotherapy.

Ankylosing spondylitis

Overall, the safety profile observed in patients with active ankylosing spondylitis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. No new safety findings were identified.

Atopic dermatitis

Infections

In the placebo-controlled period of the clinical studies, the frequency of infection over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 39% and 43% compared to 30% in the placebo group, respectively. The long-term rate of infections for the upadacitinib 15 mg and 30 mg groups was 98.5 and 109.6 events per 100 patient-years, respectively.

In placebo-controlled clinical studies, the frequency of serious infection over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.4% compared to 0.6% in the placebo group, respectively. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groups was 2.3 and 2.8 events per 100 patient-years, respectively.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled period of the clinical studies, all opportunistic infections (excluding TB and herpes zoster) reported were eczema herpeticum. The frequency of eczema herpeticum over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 0.7% and 0.8% compared to 0.4% in the placebo group, respectively. The long-term rate of eczema herpeticum for the upadacitinib 15 mg and 30 mg

12 groups was 1.6 and 1.8 events per 100 patient-years, respectively. One case of esophageal candidiasis was reported with upadacitinib 30 mg.

The long-term rate of herpes zoster for the upadacitinib 15 mg and 30 mg groups was 3.5 and 5.2 events per 100 patient-years, respectively. Most of the herpes zoster events involved a single dermatome and were non-serious.

Laboratory abnormalities

Dose-dependent changes in ALT increased and/or AST increased (≥ 3 x ULN), lipid parameters, CPK values (> 5 x ULN), and neutropenia (ANC < 1 x 109 cells/L) associated with upadacitinib treatment were similar to what was observed in the rheumatologic disease clinical studies.

Small increases in LDL cholesterol were observed after week 16 in atopic dermatitis studies.

Elderly

Based on limited data in atopic dermatitis patients aged 65 years and older, there was a higher rate of overall adverse reactions with the upadacitinib 30 mg dose compared to the 15 mg dose.

Paediatric population

A total of 343 adolescents aged 12 to 17 years with atopic dermatitis were treated in the Phase 3 studies, of which 167 were exposed to 15 mg. The safety profile for upadacitinib 15 mg in adolescents was similar to that in adults. The safety and efficacy of the 30 mg dose in adolescents are still being investigated.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Upadacitinib was administered in clinical studies up to doses equivalent in daily AUC to 60 mg prolonged-release once daily. Adverse reactions were comparable to those seen at lower doses and no specific toxicities were identified. Approximately 90% of upadacitinib in the systemic circulation is eliminated within 24 hours of dosing (within the range of doses evaluated in clinical studies). In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants ATC code: L04AA44

Mechanism of action

Upadacitinib is a selective and reversible Janus Kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit cytokine or growth factor signals involved in a broad range of cellular processes including inflammatory responses, hematopoiesis and immune surveillance. The JAK family of enzymes contains four members, JAK1, JAK2, JAK3 and TYK2 which work in pairs to phosphorylate

13 and activate signal transducers and activators of transcription (STATs). This phosphorylation, in turn, modulates gene expression and cellular function. JAK1 is important in inflammatory cytokine signals while JAK2 is important for red blood cell maturation and JAK3 signals play a role in immune surveillance and lymphocyte function.

In human cellular assays, upadacitinib preferentially inhibits signalling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2. Atopic dermatitis is driven by pro-inflammatory cytokines (including IL-4, IL-13, IL-22, TSLP, IL-31 and IFN-γ) that transduce signals via the JAK1 pathway. Inhibiting JAK1 with upadacitinib reduces the signaling of many mediators which drive the signs and symptoms of atopic dermatitis such as eczematous skin lesions and pruritus.

Pharmacodynamic effects

Inhibition of IL-6 induced STAT3 and IL-7 induced STAT5 phosphorylation

In healthy volunteers, the administration of upadacitinib (immediate-release formulation) resulted in a dose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2) - induced STAT3 and IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation in whole blood. The maximal inhibition was observed 1 hour after dosing which returned to near baseline by the end of dosing interval.

Lymphocytes

In patients with rheumatoid arthritis, treatment with upadacitinib was associated with a small, transient increase in mean ALC from baseline up to week 36 which gradually returned to at or near baseline levels with continued treatment. hsCRP

In patients with rheumatoid arthritis, treatment with upadacitinib was associated with decreases from baseline in mean hsCRP levels as early as week 1 which were maintained with continued treatment.

Clinical efficacy and safety

Rheumatoid arthritis

The efficacy and safety of upadacitinib 15 mg once daily was assessed in five Phase 3 randomised, double-blind, multicentre studies in patients with moderately to severely active rheumatoid arthritis and fulfilling the ACR/EULAR 2010 classification criteria (see Table 3). Patients 18 years of age and older were eligible to participate. The presence of at least 6 tender and 6 swollen joints and evidence of systemic inflammation based on elevation of hsCRP was required at baseline. All studies included long-term extensions for up to 5 years.

The primary analysis for each of these studies included all randomised subjects who received at least 1 dose of upadacitinib or placebo, and non-responder imputation was used for categorical endpoints.

Across the Phase 3 studies, the efficacy seen with upadacitinib 15 mg QD was generally similar to that observed with upadacitinib 30 mg QD.

Table 3: Clinical trials summary

Study name Population (n) Treatment arms Key outcome measures SELECT-EARLY MTX-naïvea  Upadacitinib 15 mg  Primary endpoint: clinical remission (947)  Upadacitinib 30 mg (DAS28-CRP) at week 24  MTX  Low disease activity (DAS28-CRP)  ACR50 Monotherapy  Radiographic progression (mTSS)

14  Physical function (HAQ-DI)  SF-36 PCS

SELECT- MTX-IRb  Upadacitinib 15 mg  Primary endpoint: low disease activity MONOTHERAPY (648)  Upadacitinib 30 mg (DAS28-CRP) at week 14  MTX  Clinical remission (DAS28-CRP)  ACR20 Monotherapy  Physical function (HAQ-DI)  SF-36 PCS  Morning stiffness SELECT-NEXT csDMARD-IRc  Upadacitinib 15 mg  Primary endpoint: low disease activity (661)  Upadacitinib 30 mg (DAS28-CRP) at week 12  Placebo  Clinical remission (DAS28-CRP)  ACR20 On background  Physical function (HAQ-DI) csDMARDs  SF-36 PCS  Low disease activity (CDAI)  Morning stiffness  FACIT-F

SELECT- MTX-IRd  Upadacitinib 15 mg  Primary endpoint: clinical remission COMPARE (1,629)  Placebo (DAS28-CRP) at week 12  Adalimumab 40 mg  Low disease activity (DAS28-CRP)  ACR20 On background MTX  Low disease activity (DAS28-CRP) vs adalimumab  Radiographic progression (mTSS)  Physical function (HAQ-DI)  SF-36 PCS  Low disease activity (CDAI)  Morning stiffness  FACIT-F SELECT- bDMARD-IRe  Upadacitinib 15 mg  Primary endpoint: low disease activity BEYOND (499)  Upadacitinib 30 mg (DAS28-CRP) at week 12  Placebo  ACR20  Physical function (HAQ-DI) On background  SF-36 PCS csDMARDs Abbreviations: ACR20 (or 50) = American College of Rheumatology ≥20% (or ≥50%) improvement; bDMARD = biologic disease-modifying anti-rheumatic drug, CRP = C-Reactive Protein, DAS28 = Disease Activity Score 28 joints, mTSS = modified Total Sharp Score, csDMARD = conventional synthetic disease-modifying anti-rheumatic drug, HAQ-DI = Health Assessment Questionnaire-Disability Index, SF-36 PCS = Short Form (36) Health Survey (SF-36) Physical Component Summary, CDAI = Clinical Disease Activity Index, FACIT-F = Functional Assessment of Chronic Illness Therapy-Fatigue score, IR = inadequate responder, MTX = methotrexate, n = number randomised a. Patients were naïve to MTX or received no more than 3 weekly MTX doses b Patients had inadequate response to MTX c Patients who had an inadequate response to csDMARDs; patients with prior exposure to at most one bDMARD were eligible (up to 20% of total number of patients) if they had either limited exposure (<3 months) or had to discontinue the bDMARD due to intolerability d Patients who had an inadequate response to MTX; patients with prior exposure to at most one bDMARD (except adalimumab) were eligible (up to 20% of total study number of patients) if they had either limited exposure (<3 months) or had to discontinue the bDMARD due to intolerability e Patients who had an inadequate response or intolerance to at least one bDMARD

15 Clinical response

Remission and low disease activity

In the studies, a significantly higher proportion of patients treated with upadacitinib 15 mg achieved low disease activity (DAS28-CRP ≤3.2) and clinical remission (DAS28-CRP <2.6) compared to placebo, MTX or adalimumab (Table 4). Compared to adalimumab, significantly higher rates of low disease activity were achieved at week 12 in SELECT-COMPARE. Overall, both low disease activity and clinical remission rates were consistent across patient populations, with or without MTX.

ACR response

In all studies, more patients treated with upadacitinib 15 mg achieved ACR20, ACR50, and ACR70 responses at 12 weeks compared to placebo, MTX, or adalimumab (Table 4). Time to onset of efficacy was rapid across measures with greater responses seen as early as week 1 for ACR20. Durable response rates were observed (with or without MTX), with ACR20/50/70 responses maintained for at least 1 year.

Treatment with upadacitinib 15 mg, alone or in combination with csDMARDs, resulted in improvements in individual ACR components, including tender and swollen joint counts, patient and physician global assessments, HAQ-DI, pain assessment and hsCRP.

Table 4: Response and remission

SELECT SELECT SELECT SELECT SELECT EARLY MONO NEXT COMPARE BEYOND Study MTX-Naїve MTX-IR csDMARD-IR MTX-IR bDMARD-IR UPA UPA UPA UPA ADA UPA MTX 15mg MTX 15mg PBO 15mg PBO 15mg 40mg PBO 15mg N 314 317 216 217 221 221 651 651 327 169 164 Week LDA DAS28-CRP ≤3.2 (% of patients) 12a/14b 28 53g 19 45e 17 48e 14 45e,h 29 14 43e 24c26d 32 60f 18 55g,h 39 48 39 59g 50h 35 CR DAS28-CRP <2.6 (% of patients) 12a/14b 14 36g 8 28e 10 31e 6 29e,h 18 9 29g 24c26d 18 48e 9 41g,h 27 48 29 49g 38i 28 ACR20 (% of patients) 12a/14b 54 76g 41 68e 36 64e 36 71e,j 63 28 65e 24c/26d 59 79g 36 67g,i 57 48 57 74g 65i 54 ACR50 (% of patients) 12a/14b 28 52g 15 42g 15 38g 15 45g,h 29 12 34g 24c/26d 33 60e 21 54g,h 42 48 43 63g 49i 40 ACR70 (% of patients) 12a/14b 14 32g 3 23g 6 21g 5 25g,h 13 7 12 24c/26d 18 44g 10 35g,h 23 48 29 51g 36h 23 CDAI ≤10 (% of patients)

16 12a/14b 30 46g 25 35l 19 40e 16 40e,h 30 14 32g 24c/26d 38 56g 22 53g,h 38 48 43 60g 47h 34 Abbreviations: ACR20 (or 50 or 70) = American College of Rheumatology ≥20% (or ≥50% or ≥70%) improvement; ADA = adalimumab; CDAI = Clinical Disease Activity Index; CR = Clinical Remission; CRP = C-Reactive Protein, DAS28 = Disease Activity Score 28 joints; IR = inadequate responder; LDA = Low Disease Activity; MTX = methotrexate; PBO = placebo; UPA= upadacitinib a SELECT-NEXT, SELECT-EARLY, SELECT-COMPARE, SELECT-BEYOND b SELECT-MONOTHERAPY c SELECT-EARLY d SELECT-COMPARE e multiplicity-controlled p≤0.001upadacitinib vs placebo or MTX comparison f multiplicity-controlled p≤0.01 upadacitinib vs placebo or MTX comparison g nominal p≤0.001 upadacitinib vs placebo or MTX comparison h nominal p≤0.001upadacitinib vs adalimumab comparison i nominal p≤0.01 upadacitinib vs adalimumab comparison j nominal p<0.05 upadacitinib vs adalimumab comparison k nominal p≤0.01 upadacitinib vs placebo or MTX comparison l nominal p<0.05 upadacitinib vs MTX comparison Note: Week 48-data derived from analysis on Full Analysis set (FAS) by randomised group using Non- Responder Imputation

Radiographic response

Inhibition of progression of structural joint damage was assessed using the modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score, at weeks 24/26 and week 48 in SELECT-EARLY and SELECT-COMPARE.

Treatment with upadacitinib 15 mg resulted in significantly greater inhibition of the progression of structural joint damage compared to placebo in combination with MTX in SELECT-COMPARE and as monotherapy compared to MTX in SELECT-EARLY (Table 5). Analyses of erosion and joint space narrowing scores were consistent with the overall scores. The proportion of patients with no radiographic progression (mTSS change ≤ 0) was significantly higher with upadacitinib 15 mg in both studies.

Table 5: Radiographic changes

SELECT SELECT EARLY COMPARE Study MTX-Naїve MTX-IR UPA UPA ADA Treatment Group MTX 15 mg PBOa 15 mg 40 mg Modified Total Sharp Score, mean change from baseline Week 24b/26c 0.7 0.1f 0.9 0.2g 0.1 Week 48 1.0 0.03e 1.7 0.3e 0.4 Proportion of patients with no radiographic progressiond Week 24b/26c 77.7 87.5f 76.0 83.5f 86.8 Week 48 74.3 89.9e 74.1 86.4e 87.9 Abbreviations: ADA = adalimumab; IR = inadequate responder; MTX = methotrexate; PBO = placebo; UPA= upadacitinib a All placebo data at week 48 derived using linear extrapolation b SELECT-EARLY c SELECT-COMPARE d No progression defined as mTSS change ≤ 0 e nominal p≤0.001 upadacitinib vs placebo or MTX comparison

17 f multiplicity-controlled p≤0.01 upadacitinib vs placebo or MTX comparison g multiplicity-controlled p≤0.001 upadacitinib vs placebo or MTX comparison

Physical function response and health-related outcomes

Treatment with upadacitinib 15 mg, alone or in combination with csDMARDs, resulted in a significantly greater improvement in physical function compared to all comparators as measured by HAQ-DI (see Table 6).

Table 6: Mean change from baseline in HAQ-DIa,b

SELECT SELECT SELECT SELECT SELECT EARLY MONO NEXT COMPARE BEYOND Study MTX-Naїve MTX-IR csDMARD-IR MTX-IR BIO-IR Treatment UPA UPA UPA UPA ADA UPA group MTX 15mg MTX 15mg PBO 15mg PBO 15mg 40mg PBO 15mg N 313 317 216 216 220 216 648 644 324 165 163 Baseline score, 1.6 1.6 1.5 1.5 1.4 1.5 1.6 1.6 1.6 1.6 1.7 mean Week -0.5 -0.8h -0.3 -0.7g -0.3 -0.6g -0.3 -0.6g,i -0.5 -0.2 -0.4g 12c/14d Week -0.6 -0.9g -0.3 -0.7h,i -0.6 24e/26f Abbreviations: ADA = adalimumab; HAQ-DI = Health Assessment Questionnaire-Disability Index; IR = inadequate responder; MTX = methotrexate; PBO = placebo; UPA = upadacitinib a Data shown are mean b Health Assessment Questionnaire-Disability Index: 0=best, 3=worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. c SELECT-EARLY, SELECT-NEXT, SELECT-COMPARE, SELECT-BEYOND d SELECT-MONOTHERAPY e SELECT-EARLY f SELECT-COMPARE g multiplicity-controlled p≤0.001 upadacitinib vs placebo or MTX comparison h nominal p≤0.001 upadacitinib vs placebo or MTX comparison i nominal p≤0.01 upadacitinib vs adalimumab comparison

In the studies SELECT-MONOTHERAPY, SELECT-NEXT, and SELECT-COMPARE, treatment with upadacitinib 15 mg resulted in a significantly greater improvement in the mean duration of morning joint stiffness compared to placebo or MTX.

In the clinical studies, upadacitinib-treated patients reported significant improvements in patient- reported quality of life, as measured by the Short Form (36) Health Survey (SF-36) Physical Component Summary compared to placebo and MTX. Moreover, upadacitinib-treated patients reported significant improvements in fatigue, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) compared to placebo.

Psoriatic arthritis

The efficacy and safety of upadacitinib 15 mg once daily were assessed in two Phase 3 randomised, double-blind, multicenter, placebo-controlled studies in patients 18 years of age or older with moderately to severely active psoriatic arthritis. All patients had active psoriatic arthritis for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender joints and at least 3 swollen joints, and active plaque psoriasis or history of plaque psoriasis. For both

18 studies, the primary endpoint was the proportion of patients who achieved an ACR20 response at week 12. SELECT-PsA 1 was a 24-week trial in 1705 patients who had an inadequate response or intolerance to at least one non-biologic DMARD. At baseline, 1393 (82%) of patients were on at least one concomitant non-biologic DMARD; 1084 (64%) of patients received concomitant MTX only; and 311 (18%) of patients were on monotherapy. Patients received upadacitinib 15 mg or 30 mg once daily, adalimumab, or placebo. At week 24, all patients randomised to placebo were switched to upadacitinib 15 mg or 30 mg once daily in a blinded manner. SELECT-PsA 1 included a long-term extension for up to 5 years.

SELECT-PsA 2 was a 24-week trial in 642 patients who had an inadequate response or intolerance to at least one biologic DMARD. At baseline, 296 (46%) of patients were on at least one concomitant non-biologic DMARD; 222 (35%) of patients received concomitant MTX only; and 345 (54%) of patients were on monotherapy. Patients received upadacitinib 15 mg or 30 mg once daily or placebo. At week 24, all patients randomised to placebo were switched to upadacitinib 15 mg or 30 mg once daily in a blinded manner. SELECT-PsA 2 included a long-term extension for up to 3 years.

Clinical response

In both studies, a statistically significant greater proportion of patients treated with upadacitinib 15 mg achieved ACR20 response compared to placebo at week 12 (Table 7). Time to onset of efficacy was rapid across measures with greater responses seen as early as week 2 for ACR20.

Treatment with upadacitinib 15 mg resulted in improvements in individual ACR components, including tender/painful and swollen joint counts, patient and physician global assessments, HAQ-DI, pain assessment, and hsCRP compared to placebo.

In SELECT-PsA 1, upadacitinib 15 mg achieved non-inferiority compared to adalimumab in the proportion of patients achieving ACR20 response at week 12; however, superiority to adalimumab could not be demonstrated.

In both studies, consistent responses were observed alone or in combination with methotrexate for primary and key secondary endpoints.

The efficacy of upadacitinib 15 mg was demonstrated regardless of subgroups evaluated including baseline BMI, baseline hsCRP, and number of prior non-biologic DMARDs (≤ 1 or >1).

Table 7: Clinical response in SELECT-PsA 1 and SELECT-PsA 2

Study SELECT-PsA 1 SELECT-PsA 2 non-biologic DMARD-IR bDMARD-IR Treatment Group PBO UPA ADA PBO UPA 15 mg 40 mg 15 mg N 423 429 429 212 211 ACR20, % of patients (95% CI) Week 12 36 (32, 41) 71 (66, 75)f 65 (61, 70) 24 (18, 30) 57 (50, 64) Difference from - 35 (28, 41)d,e 33 (24, 42)d,e placebo (95% CI) Week 24 45 (40, 50) 73 (69, 78) 67 (63, 72) 20 (15, 26) 59 (53, 66) Week 56 74 (70, 79) 69 (64, 73) 60 (53, 66) ACR50, % of patients (95% CI) Week 12 13 (10, 17) 38 (33, 42) 38 (33, 42) 5 (2, 8) 32 (26, 38) Week 24 19 (15, 23) 52 (48, 57) 44 (40, 49) 9 (6, 13) 38 (32, 45) Week 56 60 (55, 64) 51 (47, 56) 41 (34, 47)

19 ACR70, % of patients (95% CI) Week 12 2 (1, 4) 16 (12, 19) 14 (11, 17) 1 (0, 1) 9 (5, 12) Week 24 5 (3, 7) 29 (24, 33) 23 (19, 27) 1 (0, 2) 19 (14, 25) Week 56 41 (36, 45) 31 (27, 36) 24 (18, 30) MDA, % of patients (95% CI) Week 12 6 (4, 9) 25 (21, 29) 25 (21, 29) 4 (2, 7) 17 (12, 22) Week 24 12 (9, 15) 37 (32, 41)e 33 (29, 38) 3 (1, 5) 25 (19, 31)e Week 56 45 (40, 50) 40 (35, 44) 29 (23, 36) Resolution of enthesitis (LEI=0), % of patients (95% CI)a Week 12 33 (27, 39) 47 (42, 53) 47 (41, 53) 20 (14, 27) 39 (31, 47) Week 24 32 (27, 39) 54 (48, 60)e 47 (42, 53) 15 (9, 21) 43 (34, 51) Week 56 59 (53, 65) 54 (48, 60) 43 (34, 51) Resolution of dactylitis (LDI=0), % of patients (95% CI)b Week 12 42 (33, 51) 74 (66, 81) 72 (64, 80) 36 (24, 48) 64 (51, 76) Week 24 40 (31, 48) 77 (69, 84) 74 (66, 82) 28 (17, 39) 58 (45, 71) Week 56 75 (68, 82) 74 (66, 82) 51 (38, 64) PASI75, % of patients (95% CI)c Week 16 21 (16, 27) 63 (56, 69)e 53 (46, 60) 16 (10, 22) 52 (44, 61)e Week 24 27 (21, 33) 64 (58, 70) 59 (52, 65) 19 (12, 26) 54 (45, 62) Week 56 65 (59, 72) 61 (55, 68) 52 (44, 61) PASI90, % of patients (95% CI)c Week 16 12 (8, 17) 38 (32, 45) 39 (32, 45) 8 (4, 13) 35 (26, 43) Week 24 17 (12, 22) 42 (35, 48) 45 (38, 52) 7 (3, 11) 36 (28, 44) Week 56 49 (42, 56) 47 (40, 54) 41 (32, 49) Abbreviations: ACR20 (or 50 or 70) = American College of Rheumatology ≥20% (or ≥50% or ≥70%) improvement, ADA = adalimumab; bDMARD = biologic disease-modifying anti- rheumatic drug; IR = inadequate responder; MDA = minimal disease activity; PASI75 (or 90) = ≥75% (or ≥90%) improvement in Psoriasis Area and Severity Index; PBO = placebo; UPA= upadacitinib Patients who discontinued randomised treatment or were missing data at week of evaluation were imputed as non-responders in the analyses. For MDA, resolution of enthesitis, and resolution of dactylitis at week 24/56, the subjects rescued at week 16 were imputed as non-responders in the analyses.

a In patients with enthesitis at baseline (n=241, 270, and 265, respectively, for SELECT-PsA 1 and n=144 and 133, respectively, for SELECT-PsA 2) b In patients with dactylitis at baseline (n=126, 136, and 127, respectively, for SELECT-PsA 1 and n=64 and 55, respectively, for SELECT-PsA 2) c In patients with ≥ 3% BSA psoriasis at baseline (n=211, 214, and 211, respectively, for SELECT-PsA 1 and n=131 and 130, respectively, for SELECT-PsA 2) d primary endpoint e multiplicity-controlled p≤0.001 upadacitinib vs placebo comparison f multiplicity-controlled p≤0.001 upadacitinib vs adalimumab comparison (non-inferiority test)

Radiographic response

In SELECT-PsA 1, inhibition of progression of structural damage was assessed radiographically and expressed as the change from baseline in modified Total Sharp Score (mTSS) and its components, the erosion score and the joint space narrowing score, at week 24.

Treatment with upadacitinib 15 mg resulted in statistically significant greater inhibition of the progression of structural joint damage compared to placebo at week 24 (Table 8). Erosion and joint space narrowing scores were consistent with the overall scores. The proportion of patients with no

20 radiographic progression (mTSS change ≤ 0.5) was higher with upadacitinib 15 mg compared to placebo at week 24.

Table 8: Radiographic changes in SELECT-PsA 1

Treatment Group PBO UPA ADA 15 mg 40 mg Modified Total Sharp Score, mean change from baseline (95% CI) Week 24 0.25 (0.13, 0.36) -0.04 (-0.16, 0.07)c 0.01 (-0.11, 0.13) Week 56a 0.44 (0.29, 0.59) -0.05 (-0.20, 0.09) -0.06 (-0.20, 0.09) Proportion of patients with no radiographic progressionb, % (95% CI) Week 24 92 (89, 95) 96 (94, 98) 95 (93, 97) Week 56a 89 (86, 92) 97 (96, 99) 94 (92, 97) Abbreviations: ADA = adalimumab; PBO = placebo; UPA= upadacitinib a All placebo data at week 56 derived using linear extrapolation b No progression defined as mTSS change ≤0.5 c multiplicity-controlled p≤0.001 upadacitinib vs placebo comparison

Physical function response and health-related outcomes

In SELECT-PsA 1, patients treated with upadacitinib 15 mg showed statistically significant improvement from baseline in physical function as assessed by HAQ-DI at week 12 (-0.42 [95% CI: - 0.47, -0.37]) compared to placebo (-0.14 [95% CI: -0.18, -0.09]); improvement in patients treated with adalimumab was -0.34 (95% CI: -0.38, -0.29). In SELECT-PsA 2, patients treated with upadacitinib 15 mg showed statistically significant improvement from baseline in HAQ-DI at week 12 (-0.30 [95% CI: -0.37, -0.24]) compared to placebo (-0.10 [95% CI: -0.16, -0.03]). Improvement in physical function was maintained through week 56 in both studies.

Health-related quality of life was assessed by SF-36v2. In both studies, patients receiving upadacitinib 15 mg experienced statistically significant greater improvement from baseline in the Physical Component Summary score compared to placebo at week 12. Improvements from baseline were maintained through week 56 in both studies.

Patients receiving upadacitinib 15 mg experienced statistically significant improvement from baseline in fatigue, as measured by FACIT-F score, at week 12 compared to placebo in both studies. Improvements from baseline were maintained through week 56 in both studies.

At baseline, psoriatic spondylitis was reported in 31% and 34% of patients in SELECT-PsA 1 and SELECT-PsA 2, respectively. Patients with psoriatic spondylitis treated with upadacitinib 15 mg showed improvements from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores compared to placebo at week 24. Improvements from baseline were maintained through week 56 in both studies.

Ankylosing spondylitis

The efficacy and safety of upadacitinib 15 mg once daily were assessed in a randomised, double-blind, multicenter, placebo-controlled study in patients 18 years of age or older with active ankylosing spondylitis based upon the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 and Patient’s Assessment of Total Back Pain score ≥4. The study included a long-term extension for up to 2 years.

SELECT-AXIS 1 was a 14-week trial in 187 ankylosing spondylitis patients with an inadequate response to at least two Nonsteroidal Anti-inflammatory Drugs (NSAIDs) or intolerance to or contraindication for NSAIDs and had no previous exposure to biologic DMARDs. At baseline,

21 patients had symptoms of ankylosing spondylitis for an average of 14.4 years and approximately 16% of the patients were on a concomitant csDMARD. Patients received upadacitinib 15 mg once daily or placebo. At week 14, all patients randomised to placebo were switched to upadacitinib 15 mg once daily. The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14.

Clinical response

In SELECT-AXIS 1, a significantly greater proportion of patients treated with upadacitinib 15 mg achieved an ASAS40 response compared to placebo at week 14 (Table 9). A numerical difference between treatment groups was observed at week 2 and response was maintained through week 64.

Treatment with upadacitinib 15 mg resulted in improvements in individual ASAS components (patient global assessment of disease activity, total back pain assessment, inflammation, and function) and other measures of disease activity, including hsCRP, at week 14 compared to placebo.

The efficacy of upadacitinib 15 mg was demonstrated regardless of subgroups evaluated including gender, baseline BMI, symptom duration of AS, and baseline hsCRP.

Table 9: Clinical response in SELECT-AXIS 1

Treatment Group PBO UPA 15 mg N 94 93 ASAS40, % of patients (95% CI)a Week 14 25.5 (16.7, 34.3) 51.6 (41.5, 61.8) Difference from placebo (95% CI) 26.1 (12.6, 39.5)b,c ASAS20, % of patients (95% CI)a Week 14 40.4 (30.5, 50.3) 64.5 (54.8, 74.2)e ASAS Partial Remission, % of patients (95% CI) Week 14 1.1 (0.0, 3.1) 19.4 (11.3, 27.4)c BASDAI 50, % of patients (95% CI) Week 14 23.4 (14.8, 32.0) 45.2 (35.0, 55.3)d Change from baseline in ASDAS-CRP (95% CI) Week 14 -0.54 (-0.71, -0.37) -1.45 (-1.62, -1.28)c ASDAS Inactive Disease, % of patients (95% CI) Week 14 0 16.1 (8.7, 23.6)e ASDAS Low Disease Activity, % of patients (95% CI)f Week 14 10.6 (4.4, 16.9) 49.5 (39.3, 59.6)e ASDAS Major Improvement, % of patients (95% CI) Week 14 5.3 (0.8, 9.9) 32.3 (22.8, 41.8)e Abbreviations: ASAS20 (or ASAS40) = Assessment of SpondyloArthritis international Society ≥20% (or ≥40%) improvement; ASDAS-CRP = Ankylosing Spondylitis Disease Activity Score C-Reactive Protein; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; PBO = placebo; UPA= upadacitinib a An ASAS20 (ASAS40) response is defined as a ≥20% (≥40%) improvement and an absolute improvement from baseline of ≥1 (≥2) unit(s) (range 0 to 10) in ≥3 of 4 domains (Patient Global, Total Back Pain, Function, and Inflammation), and no worsening in the potential remaining domain (defined as worsening ≥20% and ≥1 unit for ASAS20 or defined as worsening of > 0

22 units for ASAS40). b primary endpoint c multiplicity-controlled p≤0.001 upadacitinib vs placebo comparison d multiplicity-controlled p≤0.01 upadacitinib vs placebo comparison e comparison not multiplicity-controlled f post-hoc analysis, not multiplicity-controlled For binary endpoints, week 14 results are based on non-responder imputation analysis. For continuous endpoints, week 14 results are based on the least squares mean change from baseline using mixed models for repeated measures analysis.

Physical function response

Patients treated with upadacitinib 15 mg showed significant improvement in physical function from baseline compared to placebo as assessed by the BASFI at week 14.

Objective measure of inflammation

Signs of inflammation were assessed by MRI and expressed as change from baseline in the SPARCC score for spine. At week 14, significant improvement of inflammatory signs in the spine was observed in patients treated with upadacitinib 15 mg compared to placebo.

Atopic dermatitis

The efficacy and safety of upadacitinib 15 mg and 30 mg once daily was assessed in three Phase 3 randomised, double-blind, multicentre studies (MEASURE UP 1, MEASURE UP 2 and AD UP) in a total of 2584 patients (12 years of age and older). Upadacitinib was evaluated in 344 adolescent and 2240 adult patients with moderate to severe atopic dermatitis (AD) not adequately controlled by topical medication(s). At baseline, patients had to have all the following: an Investigator's Global Assessment (vIGA-AD) score ≥ 3 in the overall assessment of AD (erythema, induration/papulation, and oozing/crusting) on an increasing severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16 (composite score assessing extent and severity of erythema, oedema/papulation, scratches and lichenification across 4 different body sites), a minimum body surface area (BSA) involvement of ≥ 10%, and weekly average Worst Pruritus Numerical Rating Scale (NRS) ≥ 4.

In all three studies, patients received upadacitinib once daily doses of 15 mg, 30 mg or matching placebo for 16 weeks. In the AD UP study, patients also received concomitant topical corticosteroids (TCS). Following completion of the double blinded period, patients originally randomised to upadacitinib were to continue receiving the same dose until week 260. Patients in the placebo group were re-randomised in a 1:1 ratio to receive upadacitinib 15 mg or 30 mg until week 260.

Baseline characteristics

In the monotherapy studies (MEASURE UP 1 and 2), 50.0% of patients had a baseline vIGA-AD score of 3 (moderate) and 50.0% of patients had a baseline vIGA-AD of 4 (severe). The mean baseline EASI score was 29.3 and the mean baseline weekly average Worst Pruritus NRS was 7.3. In the concomitant TCS study (AD UP), 47.1% of patients had a baseline vIGA-AD score of 3 (moderate) and 52.9% of patients had a baseline vIGA-AD of 4 (severe). The mean baseline EASI score was 29.7 and the mean baseline weekly average Worst Pruritus NRS was 7.2.

Clinical response

Monotherapy (MEASURE UP 1 AND MEASURE UP 2) and Concomitant TCS (AD UP) studies

A significantly greater proportion of patients treated with upadacitinib 15 mg or 30 mg achieved vIGA-AD 0 or 1, EASI 75, or a ≥ 4-point improvement on the Worst Pruritus NRS compared to placebo at week 16. Rapid improvements in skin clearance and itch were also achieved (see Table 10).

23 Figure 1 shows the proportion of patients achieving an EASI 75 response and mean percent change from baseline in Worst Pruritus NRS, respectively up to week 16 for MEASURE UP 1 and 2.

Table 10: Efficacy results of upadacitinib

Study MEASURE UP 1 MEASURE UP 2 AD UP Treatment PBO UPA UPA PBO UPA UPA PBO + UPA UPA Group 15 mg 30 mg 15 mg 30 mg TCS 15 mg 30 mg + + TCS TCS Number of subjects 281 281 285 278 276 282 304 300 297 randomised

Week 16 endpoints, % responders (95% CI) vIGA-AD 8 48d 62d 5 39d 52d 11 40d 59d 0/1a,b (5,12) (42,54) (56,68) (2,7) (33,45) (46,58) (7,14) (34,45) (53,64) (co-primary) EASI 75a 16 70d 80d 13 60d 73d 26 65d 77d (co-primary) (12,21) (64,75) (75,84) (9,17) (54,66) (68,78) (21,31) (59,70) (72,82)

EASI 90a 8 53d 66d 5 42d 58d 13 43d 63d (5,11) (47,59) (60,71) (3,8) (37,48) (53,64) (9,17) (37,48) (58,69)

EASI 100a 2 17d 27d 1 14d 19d 1 12e 23d (0,3) (12,21) (22,32) (0,2) (10,18) (14,23) (0,3) (8,16) (18,27)

Worst Pruritus 12 52d 60d 9 42d 60d 15 52d 64d NRSc (8,16) (46,58) (54,66) (6,13) (36,48) (54,65) (11,19) (46,58) (58,69) (≥ 4-point improvement) Early onset endpoints, % responders (95% CI) EASI 75a 4 38d 47d 4 33d 44d 7 31d 44d (Week 2) (1,6) (32,44) (42,53) (1,6) (27,39) (38,50) (4,10) (26,36) (38,50) Worst Pruritus 0 15d 20d 1 7d 16d 3 12d 19d NRS (0,1) (11,19) (15,24) (0,2) (4,11) (11,20) (1,5) (8,16) (15,24) (≥ 4-point improvement at week 1)c,f Abbreviations: UPA= upadacitinib (RINVOQ); PBO = placebo Subjects with rescue medication or with missing data were counted as non-responders. The number and percentage of subjects who were imputed as non-responders for EASI 75 and vIGA-AD 0/1 at Week 16 due to the use of rescue therapy in the placebo, upadacitinib 15 mg, and upadacitinib 30 mg groups, respectively, were 132 (47.0%), 31 (11.0%), 16 (5.6%) in MEASURE UP 1, 119 (42.8%), 24 (8.7%), 16 (5.7%) in MEASURE UP 2, and 78 (25.7%), 15 (5.0%), 14 (4.7%) in AD UP. a Based on number of subjects randomised b Responder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on a 0-4 ordinal scale c Results shown in subset of patients eligible for assessment (patients with Worst Pruritus NRS ≥ 4 at baseline) d Statistically significant vs. placebo with p < 0.001 e p < 0.001 vs placebo, without multiplicity control f Statistically significant improvements vs placebo were seen as early as 1 day after initiating upadacitinib 30 mg and 2 days after initiating upadacitinib 15 mg in MEASURE UP 1 and 2

24 Figure 1: Proportion of patients achieving an EASI 75 response and mean percent change from baseline in Worst Pruritus NRS in MEASURE UP 1 and MEASURE UP 2

Proportion of patients achieving an Mean percent change from baseline in EASI 75 response Worst Pruritus NRS ) % l ( a

% e v 5 r n i e 9 l l

t e a d n s v I n a

r a e e

B t c ) n n m I e %

o ( d e

r i c e f f t n n e a e o g d R n i C

f e a s n h % n o C 5 o

C 9 t p s n d e e n c R a r e P

Weeks Weeks Placebo Placebo RINVOQ 15 mg QD RINVOQ 15 mg QD RINVOQ 30 mg QD RINVOQ 30 mg QD *: p < 0.001 vs placebo, without multiplicity control **: statistically significant vs. placebo with p < 0.001

Treatment effects in subgroups (weight, age, gender, race, and prior systemic treatment with immunosuppressants) were consistent with the results in the overall study population.

Results at week 16 continued to be maintained through week 52 in patients treated with upadacitinib 15 mg or 30 mg.

Quality of life/patient-reported outcomes

Table 11: Patient-reported outcomes results of upadacitinib at week 16

Study MEASURE UP 1 MEASURE UP 2 Treatment group PBO UPA UPA PBO UPA UPA 15 mg 30 mg 15 mg 30 mg Number of subjects 281 281 285 278 276 282 randomised % responders (95% CI) ADerm-SS Skin Pain 15 54 e 63e 13 49e 65e (≥ 4-point improvement)a (10,20) (47,60) (57,69) (9,18) (43,56) (59,71)

ADerm-IS Sleep 13 55e 66e 12 50e 62e (≥ 12-point improvement) a,b (9,18) (48,62) (60,72) (8,17) (44,57) (56,69) DLQI 0/1c 4 30e 41e 5 24e 38e (2,7) (25,36) (35,47) (2,7) (19,29) (32,44) HADS Anxiety <8 and 14 46e 49e 11 46e 56e HADS Depression < 8d (8,20) (37,54) (41,57) (6,17) (38,54) (48,64)

25 Study MEASURE UP 1 MEASURE UP 2 Abbreviations: UPA= upadacitinib (RINVOQ); PBO = placebo; DLQI = Dermatology Life Quality Index; HADS = Hospital Anxiety and Depression Scale Subjects with rescue medication or with missing data were counted as non-responders. The threshold values specified correspond to the minimal clinically important difference (MCID) and was used to determine response. a Results shown in subset of patients eligible for assessment (patients with assessment score > MCID at baseline). b ADerm-IS Sleep assesses difficulty falling asleep, sleep impact, and waking up at night due to AD. c Results shown in subset of patients eligible for assessment (patients with DLQI > 1 at baseline). d Results shown in subset of patients eligible for assessment (patients with HADS Anxiety ≥ 8 or HADS Depression ≥ 8 at baseline) e Statistically significant vs. placebo with p < 0.001

Paediatric population

A total of 344 adolescents aged 12 to 17 years with moderate to severe atopic dermatitis were randomised across the three Phase 3 studies to receive either 15 mg (N=114) or 30 mg (N=114) upadacitinib or matching placebo (N=116), in monotherapy or combination with topical corticosteroids. Efficacy was consistent between the adolescents and adults. The safety profile in adolescents was generally similar to that in adults, with dose dependent increases in the rate of some adverse events, including neutropenia and herpes zoster. At both doses, the rate of neutropenia was slightly increased in adolescents compared to adults. The rate of herpes zoster in adolescents at the 30 mg dose was comparable to that in adults. The safety and efficacy of the 30 mg dose in adolescents are still being investigated.

Table 12: Efficacy results of upadacitinib for adolescents at week 16

Study MEASURE UP 1 MEASURE UP 2 AD UP Treatment Group PBO UPA PBO UPA PBO + UPA 15 mg 15 mg TCS 15 mg + TCS Number of adolescent subjects 40 42 36 33 40 39 randomised % responders (95% CI) vIGA-AD 0/1 a,b 8 38 3 42 8 31 (0,16) (23,53) (0,8) (26,59) (0,16) (16,45) EASI 75a 8 71 14 67 30 56 (0,17) (58,85) (3,25) (51,83) (16,44) (41,72) Worst Pruritus 15 45 3 33 13 42 NRSc (4,27) (30,60) (0,8) (16,50) (2,24) (26,58) (≥ 4-point improvement)

26 Abbreviations: UPA= upadacitinib (RINVOQ); PBO = placebo Subjects with rescue medication or with missing data were counted as non-responders. a Based on number of subjects randomised b Responder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on a 0-4 ordinal scale. c Results shown in subset of patients eligible for assessment (patients with Worst Pruritus NRS ≥ 4 at baseline).

The European Medicines Agency has deferred the obligation to submit the results of studies with RINVOQ in one or more subsets of the paediatric population in chronic idiopathic arthritis (including rheumatoid arthritis, psoriatic arthritis, spondyloarthritis and juvenile idiopathic arthritis) and atopic dermatitis (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after multiple once daily administrations.

Absorption

Following oral administration of upadacitinib prolonged-release formulation, upadacitinib is absorbed with a median Tmax of 2 to 4 hours. Coadministration of upadacitinib with a high-fat meal had no clinically relevant effect on upadacitinib exposures (increased AUC by 29% and Cmax by 39%). In clinical trials, upadacitinib was administered without regard to meals (see section 4.2). In vitro, upadacitinib is a substrate for the efflux transporters P-gp and BCRP.

Distribution

Upadacitinib is 52% bound to plasma proteins. Upadacitinib partitions similarly between plasma and blood cellular components, as indicated by the blood to plasma ratio of 1.0.

Metabolism

Upadacitinib metabolism is mediated by CYP3A4 with a potential minor contribution from CYP2D6. The pharmacologic activity of upadacitinib is attributed to the parent molecule. In a human radiolabeled study, unchanged upadacitinib accounted for 79% of the total radioactivity in plasma while the main metabolite (product of monooxidation followed by glucuronidation) accounted for 13% of the total plasma radioactivity. No active metabolites have been identified for upadacitinib.

Elimination

Following single dose administration of [14C]-upadacitinib immediate-release solution, upadacitinib was eliminated predominantly as the unchanged parent substance in urine (24%) and faeces (38%). Approximately 34% of upadacitinib dose was excreted as metabolites. Upadacitinib mean terminal elimination half-life ranged from 9 to 14 hours.

Special populations

Renal impairment

Upadacitinib AUC was 18%, 33%, and 44% higher in subjects with mild (estimated glomerular filtration rate 60 to 89 mL/min/1.73 m2), moderate (estimated glomerular filtration rate 30 to 59 mL/min/1.73 m2), and severe (estimated glomerular filtration rate 15 to 29 mL/min/1.73 m2) renal impairment, respectively, compared to subjects with normal renal function. Upadacitinib Cmax was similar in subjects with normal and impaired renal function. Mild or moderate renal impairment has no

27 clinically relevant effect on upadacitinib exposure following the 15 mg or 30 mg once daily dosing regimens. The recommended dose is 15 mg once daily for patients with severe renal impairment.

Hepatic impairment

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment has no clinically relevant effect on upadacitinib exposure. Upadacitinib AUC was 28% and 24% higher in subjects with mild and moderate hepatic impairment, respectively, compared to subjects with normal liver function. Upadacitinib Cmax was unchanged in subjects with mild hepatic impairment and 43% higher in subjects with moderate hepatic impairment compared to subjects with normal liver function. Upadacitinib was not studied in patients with severe (Child-Pugh C) hepatic impairment.

Paediatric population

The pharmacokinetics of upadacitinib have not yet been evaluated in paediatric patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis (see section 4.2).

Upadacitinib pharmacokinetics and steady-state concentrations are similar for adults and adolescents 12 to 17 years of age with atopic dermatitis. The posology in adolescent patients 30 kg to < 40 kg was determined using population pharmacokinetic modelling and simulation.

The pharmacokinetics of upadacitinib in paediatric patients (< 12 years of age) with atopic dermatitis have not been established.

Intrinsic factors

Age, sex, body weight, race, and ethnicity did not have a clinically meaningful effect on upadacitinib exposure. Upadacitinib pharmacokinetics are consistent between rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis patients.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology.

Upadacitinib, at exposures (based on AUC) approximately 4 and 10 times the clinical dose of 15 mg and 2 and 5 times the clinical dose of 30 mg in male and female Sprague-Dawley rats, respectively, was not carcinogenic in a 2-year carcinogenicity study in Sprague-Dawley rats. Upadacitinib was not carcinogenic in a 26-week carcinogenicity study in CByB6F1-Tg(HRAS)2Jic transgenic mice.

Upadacitinib was not mutagenic or genotoxic based on the results of in vitro and in vivo tests for gene mutations and chromosomal aberrations.

Upadacitinib had no effect on fertility in male or female rats at exposures up to approximately 21 and 43 times the maximum recommended human dose (MRHD) of 30 mg in males and females, respectively, on an AUC basis in a fertility and early embryonic development study. Dose-related increases in foetal resorptions associated with post-implantation losses in this fertility study in rats were attributed to the developmental/teratogenic effects of upadacitinib. No adverse effects were observed at exposures below clinical exposure (based on AUC). Post-implantation losses were observed at exposures 11 times the clinical exposure at the MRHD of 30 mg (based on AUC).

In animal embryo-foetal development studies, upadacitinib was teratogenic in both rats and rabbits. Upadacitinib resulted in increases in skeletal malformations in rats at 1.6 and 0.8 times the clinical exposure (AUC-based) at the 15 and 30 mg (MRHD) doses, respectively. In rabbits an increased incidence of cardiovascular malformations was observed at 15 and 7.6 times the clinical exposure at the 15 and 30 mg doses (AUC-based), respectively. No developmental toxicity was observed at approximately 0.15 times (rat) and at similar exposure in rabbits as the exposures at the MRHD of

28 30 mg. In a pre- and post-natal development study in pregnant female rats, oral upadacitinib administration at exposures approximately 1.4 times the MRHD of 30 mg resulted in no maternal effects, no effects on parturition, lactation or maternal behaviour and no effects on the offspring.

Following administration of upadacitinib to lactating rats, the concentrations of upadacitinib in milk over time generally paralleled those in plasma, with approximately 30-fold higher exposure in milk relative to maternal plasma. Approximately 97% of upadacitinib-related material in milk was the parent molecule, upadacitinib.

Administration of upadacitinib to juvenile Sprague-Dawley rats (from postnatal day 15 to 63) resulted in exposures and pharmacologic effects on the lymphoid system similar to those observed in adult rats. No adverse findings were observed in juvenile rats at exposures (AUC) approximately 9.4 and 4.8 times the exposures at the clinical doses of 15 mg and 30 mg, respectively (based on exposures in adult RA patients).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet contents

Microcrystalline cellulose Hypromellose Mannitol Tartaric acid Silica, colloidal anhydrous Magnesium stearate

Film coating

Poly(vinyl alcohol) Macrogol Talc Titanium dioxide (E171) Iron oxide black (E172) (15 mg strength only) Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

RINVOQ 15 mg prolonged-release tablets

Prolonged-release tablets in blisters: 2 years Prolonged-release tablets in bottles: 3 years

RINVOQ 30 mg prolonged-release tablets

Prolonged-release tablets in blisters: 2 years Prolonged-release tablets in bottles: 3 years

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

29 Store in the original blister or bottle in order to protect from moisture. Keep the bottle tightly closed.

6.5 Nature and contents of container

RINVOQ 15 mg prolonged-release tablets

Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium calendar blisters in packs containing 28 or 98 prolonged-release tablets, or multipacks containing 84 (3 packs of 28) prolonged- release tablets.

HDPE bottles with desiccant and polypropylene cap in carton containing 30 prolonged-release tablets. Pack size: 1 bottle (30 prolonged-release tablets) or 3 bottles (90 prolonged-release tablets).

Not all pack sizes may be marketed.

RINVOQ 30 mg prolonged-release tablets

Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium calendar blisters in packs containing 28 or 98 prolonged-release tablets.

HDPE bottles with desiccant and polypropylene cap in carton containing 30 prolonged-release tablets. Pack size: 1 bottle (30 prolonged-release tablets) or 3 bottles (90 prolonged-release tablets).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/001 EU/1/19/1404/002 EU/1/19/1404/003 EU/1/19/1404/004 EU/1/19/1404/005 EU/1/19/1404/006 EU/1/19/1404/007 EU/1/19/1404/008 EU/1/19/1404/009

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 December 2019

30 10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

31 ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

32 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturers responsible for batch release

AbbVie S.r.l. 148, Pontina Km 52 snc 04011 Campoverde di Aprilia (LT) ITALY

And

AbbVie Logistics B.V Zuiderzeelaan 53 8017 JV Zwolle NETHERLANDS

The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

 Additional risk minimisation measures Prior to launch of RINVOQ in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including

33 communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority.

The objective of the programme is to increase awareness of HCPs and patients on the risks of serious and opportunistic infections including TB, herpes zoster, foetal malformation (pregnancy risk), MACE, and VTEs and how to manage these risks.

The MAH shall ensure that in each Member State where RINVOQ is marketed, all healthcare professionals and patients/carers who are expected to prescribe, dispense or use RINVOQ have access to/are provided with the following educational package:

The physician educational material should contain:  The Summary of Product Characteristics  Guide for healthcare professionals  Patient Alert Card (PAC)

The Guide for healthcare professionals shall contain the following key elements:  General introductory language that the HCP measure contains important information to assist the discussion with patients when prescribing upadacitinib. The brochure also informs on steps which can be taken to reduce a patient's risk for key safety aspects of upadacitinib.  Language for HCPs to inform patients of the importance of the PAC  Risk of serious and opportunistic infections including TB o Language on the risk of infections during treatment with upadacitinib o Language on increased risk of serious infections in patients ≥ 65 years of age o Details on how to reduce the risk of infection with specific clinical measures (what laboratory parameters should be used to initiate upadacitinib, screening for tuberculosis (TB), and getting patients immunised as per local guidelines, and interruption of upadacitinib if an infection develops) o Language on avoidance of live vaccines (i.e., Zostavax) prior to and during upadacitinib treatment o Details to advise patients on signs/symptoms of infection to be aware of, so that patients can seek medical attention quickly.  Risk of herpes zoster o Language on the risk of herpes zoster during treatment with upadacitinib o Details to advise patients on signs/symptoms of infection to be aware of, so that patients can seek medical attention quickly.  Risk of foetal malformation o Language on teratogenicity of upadacitinib in animals o Details on how to reduce the risk of exposure during pregnancy for women of childbearing potential based on the following: upadacitinib is contraindicated during pregnancy, women of childbearing potential should be advised to use effective contraception both during treatment and for 4 weeks after the final dose of upadacitinib treatment, and to advise patients to inform their HCP immediately if they think they could be pregnant or if pregnancy is confirmed.  Risk of MACE o Language on the increased risk of major adverse cardiovascular event (MACE) in patients with immune-mediated inflammatory diseases and the need to consider typical CV risk factors (e.g., hypertension, hyperlipidaemia) when treating patients o Language on the risk of MACE during treatment with upadacitinib o Language on the risk of hyperlipidaemia during upadacitinib therapy o Details on monitoring of lipid levels and management of elevated lipid levels per clinical guidelines

34  Risk of VTE o Examples of the risk factors which may put a patient at higher risk for venous thromboembolic events (VTE) and in whom caution is needed when using upadacitinib. o Language on the risk of VTE during treatment with upadacitinib o Language on need for discontinuation of upadacitinib, evaluation, and appropriate treatment for VTE if clinical features of deep venous thrombosis or pulmonary embolism develop

Information for upadacitinib use in moderate to severe AD

The 30 mg upadacitinib dose in atopic dermatitis  Language on dose-dependent increase in serious infections and herpes zoster with upadacitinib.  Language on dose-dependent increase in plasma lipids with upadacitinib.  Language that eczema herpeticum occurred in both placebo and upadacitinib- treated subjects with similar rates in the 30 mg and 15 mg groups.  Language that the 30 mg dose is not recommended in certain populations (patients with severe renal impairment and patients taking strong CYP3A4 inhibitors).  Reminder that the 15 mg dose is the recommended dose in patients ≥ 65 years of age.

Upadacitinib use in adolescents 12 years and older  Reminder that live, attenuated vaccines (ie. varicella, MMR, BCG) which depending on local guidelines may be considered in adolescents. Language not to administer these vaccines immediately prior to or during upadacitinib treatment.  Language to remind adolescents of the potential pregnancy risks and on the appropriate use of effective contraception.  Language if their adolescent patient has not experienced menarche, to inform their adolescent patient or caregiver to let them know when they do.

Instructions for how to access digital HCP information Instructions on where to report AEs

The patient information pack should contain:  Patient information leaflet  A patient alert card

 The patient alert card shall contain the following key messages: o Contact details of the upadacitinib prescriber o Language that the PAC should be carried by the patient at any time and to share it with HCPs involved in their care (i.e., non-upadacitinib prescribers, emergency room HCPs, etc.) o Description of signs/symptoms of infections the patient needs to be aware of, so that they can seek attention from their HCP:  Language to advise patients and their HCPs about the risk of live vaccinations when given during upadacitinib therapy. Examples of live vaccines are provided. o Description of targeted risks for awareness by the patient and for HCPs involved in their care including:  Elevations in plasma lipids and the need for monitoring and lipid lowering treatment  A reminder to use contraception, that upadacitinib is contraindicated during pregnancy, and to notify their HCPs if they become pregnant while taking upadacitinib

35 o Description of signs/symptoms of deep venous thrombosis or pulmonary embolism which the patient needs to be aware of, so that they can seek attention from an HCP

36 ANNEX III

LABELLING AND PACKAGE LEAFLET

37 A. LABELLING

38 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Blister Carton (Individual carton)

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 15 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

28 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original blister in order to protect from moisture.

39 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 15 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC SN NN

40 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton for 84 tablet multipack (with Blue Box)

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 15 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack: 84 (3 packs of 28) prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original blister in order to protect from moisture.

41 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 15 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC SN NN

42 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Intermediate carton of 84 tablet multipack (without Blue Box)

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 15 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

28 prolonged-release tablets. Component of a multipack, can’t be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

43 9. SPECIAL STORAGE CONDITIONS

Store in the original blister in order to protect from moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 15 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

44 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton of 98 tablets

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 15 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

98 prolonged-release tablets.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original blister in order to protect from moisture.

45 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/005

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 15 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC SN NN

46 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Inner carton of 49 tablets (for the 98 pack)

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 15 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

49 prolonged-release tablets.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original blister in order to protect from moisture.

47 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/005

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 15 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

48 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 15 mg prolonged-release tablets upadacitinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Mon. Tue. Wed. Thu. Fri. Sat. Sun.

49 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Bottle Carton (30 and 90 pack)

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 15 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets 90 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use Do not chew, crush or break the tablet. Swallow whole.

Do not swallow the desiccant.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

50 9. SPECIAL STORAGE CONDITIONS

Store in the original bottle and keep the bottle tightly closed in order to protect from moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/002 EU/1/19/1404/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 15 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC SN NN

51 PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING

Bottle Label

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 15 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

Do not swallow the desiccant.

Important to open

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original bottle and keep the bottle tightly closed in order to protect from moisture.

52 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

53 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Blister Carton (Individual carton)

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 30 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

28 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original blister in order to protect from moisture.

54 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 30 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC SN NN

55 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton of 98 tablets

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 30 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

98 prolonged-release tablets.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original blister in order to protect from moisture.

56 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/009

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 30 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC SN NN

57 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Inner carton of 49 tablets (for the 98 pack)

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 30 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

49 prolonged-release tablets.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original blister in order to protect from moisture.

58 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/009

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 30 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

59 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 30 mg prolonged-release tablets upadacitinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Mon. Tue. Wed. Thu. Fri. Sat. Sun.

60 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Bottle Carton (30 and 90 pack)

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 30 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets 90 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

Do not swallow the desiccant.

QR code to be included For more information and support on taking RINVOQ go to www.rinvoq.eu

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

61 9. SPECIAL STORAGE CONDITIONS

Store in the original bottle and keep the bottle tightly closed in order to protect from moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1404/007 EU/1/19/1404/008

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE rinvoq 30 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC SN NN

62 PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING

Bottle Label

1. NAME OF THE MEDICINAL PRODUCT

RINVOQ 30 mg prolonged-release tablets upadacitinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

Do not chew, crush or break the tablet. Swallow whole.

Do not swallow the desiccant.

Important to open

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original bottle and keep the bottle tightly closed in order to protect from moisture.

63 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

64 B. PACKAGE LEAFLET

65 Package leaflet: Information for the patient

RINVOQ 15 mg prolonged-release tablets RINVOQ 30 mg prolonged-release tablets upadacitinib

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist, or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What RINVOQ is and what it is used for 2. What you need to know before you take RINVOQ 3. How to take RINVOQ 4. Possible side effects 5. How to store RINVOQ 6. Contents of the pack and other information

1. What RINVOQ is and what it is used for

RINVOQ contains the active substance upadacitinib. It belongs to a group of medicines called Janus kinase inhibitors. By reducing the activity of an enzyme called ‘Janus kinase’ in the body, RINVOQ lowers inflammation in the following diseases:

 Rheumatoid Arthritis  Psoriatic Arthritis  Ankylosing Spondylitis  Atopic Dermatitis

Rheumatoid Arthritis RINVOQ is used to treat adults with rheumatoid arthritis. Rheumatoid arthritis is a disease that causes inflamed joints. If you have moderate to severe active rheumatoid arthritis, you may first be given other medicines, one of which will usually be methotrexate. If these medicines do not work well enough, you will be given RINVOQ either alone or in combination with methotrexate to treat your rheumatoid arthritis.

RINVOQ can help to reduce pain, stiffness and swelling in your joints, reduce tiredness and it can slow down damage to the bone and cartilage in your joints. These effects can ease your normal daily activities and so improve your quality of life.

Psoriatic Arthritis RINVOQ is used to treat adults with psoriatic arthritis. Psoriatic arthritis is a disease that causes inflamed joints and psoriasis. If you have active psoriatic arthritis, you may first be given other

66 medicines. If these medicines do not work well enough, you will be given RINVOQ either alone or in combination with methotrexate to treat your psoriatic arthritis.

RINVOQ can help to reduce pain, stiffness, and swelling in and around your joints, pain and stiffness in your spine, psoriatic skin rash, and tiredness, and it can slow down damage to the bone and cartilage in your joints. These effects can ease your normal daily activities and so improve your quality of life.

Ankylosing Spondylitis RINVOQ is used to treat adults with ankylosing spondylitis. Ankylosing spondylitis is a disease that primarily causes inflammation in the spine. If you have active ankylosing spondylitis, you may first be given other medicines. If these medicines do not work well enough, you will be given RINVOQ to treat your ankylosing spondylitis.

RINVOQ can help to reduce back pain, stiffness, and inflammation in your spine. These effects can ease your normal daily activities and so improve your quality of life.

Atopic Dermatitis RINVOQ is used to treat adults and adolescents 12 years and older with moderate to severe atopic dermatitis, also known as atopic eczema. RINVOQ may be used with eczema medicines that you apply to the skin or it may be used on its own.

Taking RINVOQ can improve the condition of your skin, and reduce itching and flares. RINVOQ can help improve symptoms of pain, anxiety and depression that people with atopic dermatitis may have. RINVOQ can also help improve your sleep disturbance and overall quality of life.

2. What you need to know before you take RINVOQ

Do not take RINVOQ  if you are allergic to upadacitinib or any of the other ingredients of this medicine (listed in section 6)  if you have a severe infection (such as pneumonia or bacterial skin infection)  if you have active tuberculosis (TB)  if you have severe liver problems  if you are pregnant (see section Pregnancy, breast-feeding and contraception)

Warnings and precautions Talk to your doctor or pharmacist before and during treatment with RINVOQ if:  you have an infection (fever, sweating, or chills, shortness of breath, warm, red, or painful skin or sores on your body, feeling tired, cough, burning sensation when you pass urine or passing urine more often than normal, severe headache with stiff neck), or if you have ever had an infection that keeps coming back – RINVOQ can reduce your body’s ability to fight infections and so may worsen an infection that you already have, or make it more likely for you to get a new infection  you have had tuberculosis or have been in close contact with someone with tuberculosis. Your doctor will test you for tuberculosis before starting RINVOQ and may retest during treatment  you have had a herpes zoster infection (shingles), because RINVOQ may allow it to come back. Tell your doctor if you get a painful skin rash with blisters as these can be signs of shingles  you have ever had hepatitis B or C  you have recently had or plan to have a vaccination (immunisation) - this is because live vaccines are not recommended while using RINVOQ  you have cancer - because your doctor will have to decide if you can still be given RINVOQ  you are at high risk of developing skin cancer, your doctor may recommend preventive measures such as regular skin examinations while taking RINVOQ. Talk to your doctor if you develop a new lesion or any change in the appearance of an area on the skin. Some patients receiving RINVOQ have developed skin cancers

67  you have heart problems, high blood pressure, or high cholesterol  your liver does not work as well as it should  you have had blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism). Tell your doctor if you get a painful swollen leg, chest pain, or shortness of breath as these can be signs of blood clots in the veins  you have kidney problems.

Blood tests You will need blood tests before you start taking RINVOQ, or while you are taking it. This is to check for a low red blood cell count (anaemia), low white blood cell count (neutropaenia or lymphopaenia), high blood fat (cholesterol) or high levels of liver enzymes. The tests are to check that treatment with RINVOQ is not causing problems.

Elderly There is a higher rate of infection in patients aged 65 years and older. Tell your doctor as soon as you notice any signs or symptoms of an infection.

Children and adolescents

RINVOQ is not recommended for use in children under 12 years of age or adolescents weighing less than 30 kg with atopic dermatitis. This is because it has not been studied in these patients.

RINVOQ is not recommended for use in children and adolescents under 18 years of age with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. This is because it has not been studied in this age group.

Other medicines and RINVOQ Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because some medicines may reduce how well RINVOQ works or may increase the risk of getting side effects. It is very important to talk to your doctor or pharmacist if you are taking any of the following:  medicines to treat fungal infections (such as itraconazole, posaconazole or voriconazole)  medicines to treat bacterial infections (such as clarithromycin)  medicines to treat Cushing’s syndrome (such as ketoconazole)  medicines to treat tuberculosis (such as rifampicin)  medicines to treat seizures or fits (such as phenytoin)  medicines that affect your immune system (such as azathioprine, ciclosporin and tacrolimus)

If any of the above apply to you or you are not sure, talk to your doctor or pharmacist before taking RINVOQ.

Pregnancy, breast-feeding and contraception

Pregnancy RINVOQ must not be used during pregnancy.

Breast-feeding If you are breast-feeding or are planning to breast-feed, talk to your doctor before taking this medicine. You should not use RINVOQ while breast-feeding as it is not known if this medicine passes into breast milk. You and your doctor should decide if you will breast-feed or use RINVOQ. You should not do both.

68 Contraception If you are a woman of child-bearing potential, you must use effective contraception to avoid becoming pregnant while taking RINVOQ and for at least 4 weeks after your last dose of RINVOQ. If you become pregnant during this time, you must talk to your doctor straight away.

If your child has her first menstrual period while taking RINVOQ, you should inform the doctor.

Driving and using machines RINVOQ has no effect on the ability to drive and use machines.

3. How to take RINVOQ

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

How much to take

If you have rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

The recommended dose is one 15 mg tablet once a day.

If you have atopic dermatitis

Adults: The recommended dose is 15 mg or 30 mg as prescribed by your doctor, as one tablet once a day. Your doctor may increase or decrease your dose depending on how well the medicine is working.

Elderly: If you are 65 years of age or older, the recommended dose is 15 mg once a day.

Adolescents (from 12 to 17 years of age) weighing at least 30 kg: The recommended dose is one 15 mg tablet once a day.

How to take

 Swallow the tablet whole with water. Do not split, crush, chew or break the tablet before swallowing as it may change how much medicine gets into your body.  To help you remember to take RINVOQ, take it at the same time every day.  The tablets can be taken with or without food.  Do not swallow the desiccant.

If you take more RINVOQ than you should If you take more RINVOQ than you should, contact your doctor. You may get some of the side effects listed in section 4.

If you forget to take RINVOQ  If you miss a dose, take it as soon as you remember.  If you forget your dose for an entire day, just skip the missed dose and take only a single dose as usual the following day.  Do not take a double dose to make up for a forgotten tablet.

If you stop taking RINVOQ Do not stop taking RINVOQ unless your doctor tells you to stop taking it.

69 How to open the bottle

Foil Cutting Tool - on the cap of the bottle

1. How to puncture the foil 1a. Remove the cap from the bottle by pushing down and while still pushing, turn the cap anti-clockwise. 1b. Turn the cap over and place the cutting tool near the edge of the foil seal.

2. Push down to make a hole in the foil and move the cutting tool round the edge of the foil to continue cutting the foil.

3. When you have taken your tablet, put the cap back on and close the bottle.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, RINVOQ can cause side effects, although not everybody gets them.

Serious side effects Talk to your doctor or get medical help straight away if you get any signs of infection such as:  shingles or painful skin rash with blisters (herpes zoster) – common (may affect up to 1 in 10 people)  infection of the lung (pneumonia), which may cause shortness of breath, fever, and a cough with mucus – uncommon (may affect up to 1 in 100 people)

Other side effects Talk to your doctor if you notice any of the following side effects:

Very common (may affect more than 1 in 10 people)  throat and nose infections  acne

70 Common (may affect up to 1 in 10 people)  cough  fever  cold sores (herpes simplex)  feeling sick in the stomach (nausea)  increase in an enzyme called creatine kinase, shown by blood tests  low white blood cell counts shown in blood tests  increased levels of cholesterol (a type of fat in the blood) as shown in tests  increased levels of liver enzymes, shown by blood tests (sign of liver problems)  weight gain  inflammation (swelling) of the hair follicles  flu (influenza)  anaemia  pain in your belly (abdomen)  fatigue (feeling unusually tired and weak)  headache  hives (urticaria)

Uncommon (may affect up to 1 in 100 people)  thrush in the mouth (white patches in the mouth)  increased levels of triglycerides (a type of fat) in the blood, as shown in tests

Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store RINVOQ

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister label and carton after ‘EXP’.

This medicine does not require any special temperature storage conditions.

Store in original blister or bottle with the lid tightly closed to protect from moisture.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What RINVOQ contains

The active substance is upadacitinib.

RINVOQ 15 mg prolonged-release tablets  Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.  The other ingredients are:

71  Core tablet: microcrystalline cellulose, mannitol, tartaric acid, hypromellose, silica colloidal anhydrous, magnesium stearate.  Film coating: poly(vinyl alcohol), macrogol, talc, titanium dioxide (E171), iron oxide red (E172), iron oxide black (E172).

RINVOQ 30 mg prolonged-release tablets  Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib.  The other ingredients are:  Core tablet: microcrystalline cellulose, mannitol, tartaric acid, hypromellose, silica colloidal anhydrous, magnesium stearate.  Film coating: poly(vinyl alcohol), macrogol, talc, titanium dioxide (E171), iron oxide red (E172).

What RINVOQ looks like and contents of the pack

RINVOQ 15 mg prolonged-release tablets

RINVOQ 15 mg prolonged-release tablets are purple, oblong, biconvex tablets imprinted on one side with ‘a15’.

The tablets are provided in blisters or bottles. RINVOQ is available in packs containing 28 or 98 prolonged-release tablets and in multipacks of 84 comprising 3 cartons, each containing 28 prolonged-release tablets. Each calendar blister contains 7 tablets.

RINVOQ is available in bottles with desiccant containing 30 prolonged-release tablets, each pack contains 1 bottle (30 tablet pack) or 3 bottles (90 tablet pack).

RINVOQ 30 mg prolonged-release tablets

RINVOQ 30 mg prolonged-release tablets are red, oblong, biconvex tablets imprinted on one side with ‘a30’.

The tablets are provided in blisters or bottles.

RINVOQ is available in packs containing 28 or 98 prolonged-release tablets. Each calendar blister contains 7 tablets.

RINVOQ is available in bottles with desiccant containing 30 prolonged-release tablets, each pack contains 1 bottle (30 tablet pack) or 3 bottles (90 tablet pack).

Not all pack sizes may be marketed.

Marketing Authorisation Holder AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

Manufacturer AbbVie S.r.l. S.R. 148 Pontina, km 52 SNC 04011 Campoverde di Aprilia (Latina) Italy

72 AbbVie Logistics B.V. Zuiderzeelaan 53 Zwolle, 8017 JV, Netherlands

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva AbbVie SA AbbVie UAB Tél/Tel: +32 10 477811 Tel: +370 5 205 3023

България Luxembourg/Luxemburg АбВи ЕООД AbbVie SA Тел.:+359 2 90 30 430 Belgique/Belgien Tél/Tel: +32 10 477811

Česká republika Magyarország AbbVie s.r.o. AbbVie Kft. Tel: +420 233 098 111 Tel.:+36 1 455 8600

Danmark Malta AbbVie A/S V.J.Salomone Pharma Limited Tlf: +45 72 30-20-28 Tel: +356 22983201

Deutschland Nederland AbbVie Deutschland GmbH & Co. KG AbbVie B.V. Tel: 00800 222843 33 (gebührenfrei) Tel: +31 (0)88 322 2843 Tel: +49 (0) 611 / 1720-0

Eesti Norge AbbVie OÜ AbbVie AS Tel: +372 623 1011 Tlf: +47 67 81 80 00

Ελλάδα Österreich AbbVie ΦΑΡΜΑΚΕΥΤΙΚΗ Α.Ε. AbbVie GmbH Τηλ: +30 214 4165 555 Tel: +43 1 20589-0

España Polska AbbVie Spain, S.L.U. AbbVie Polska Sp. z o.o. Tel: +34 91 384 09 10 Tel.: +48 22 372 78 00

France Portugal AbbVie AbbVie, Lda. Tél: +33 (0) 1 45 60 13 00 Tel: +351 (0)21 1908400 Hrvatska România AbbVie d.o.o. AbbVie S.R.L. Tel + 385 (0)1 5625 501 Tel: +40 21 529 30 35

Ireland Slovenija AbbVie Limited AbbVie Biofarmacevtska družba d.o.o. Tel: +353 (0)1 4287900 Tel: +386 (1)32 08 060

73 Ísland Slovenská republika Vistor hf. AbbVie s.r.o. Tel: +354 535 7000 Tel: +421 2 5050 0777

Italia Suomi/Finland AbbVie S.r.l. AbbVie Oy Tel: +39 06 928921 Puh/Tel: +358 (0)10 2411 200

Κύπρος Sverige Lifepharma (Z.A.M.) Ltd AbbVie AB Τηλ.: +357 22 34 74 40 Tel: +46 (0)8 684 44 600

Latvija United Kingdom (Northern Ireland) AbbVie SIA AbbVie Deutschland GmbH & Co. KG Tel: +371 67605000 Tel: +44 (0)1628 561090

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.

Detailed and updated information on this product is also available by scanning the QR code included below or on the outer carton with a smart phone. The same information is also available on the following URL: www.rinvoq.eu.

QR code to be included

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